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Nitrile
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In organic chemistry, a nitrile is any organic compound that has a −C≡N functional group. The name of the compound is composed of a base, which includes the carbon of the −C≡N, suffixed with "nitrile", so for example CH3CH2C≡N is called "propionitrile" (or propanenitrile).[1] The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, including methyl cyanoacrylate, used in super glue, and nitrile rubber, a nitrile-containing polymer used in latex-free laboratory and medical gloves. Nitrile rubber is also widely used as automotive and other seals since it is resistant to fuels and oils. Organic compounds containing multiple nitrile groups are known as cyanocarbons.
Inorganic compounds containing the −C≡N group are not called nitriles, but cyanides instead.[2] Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.
Structure and basic properties
[edit]The N−C−C geometry is linear in nitriles, reflecting the sp hybridization of the triply bonded carbon. The C−N distance is short at 1.16 Å, consistent with a triple bond.[3] Nitriles are polar, as indicated by high dipole moments. As liquids, they have high relative permittivities, often in the 30s.
History
[edit]The first compound of the homolog row of nitriles, the nitrile of formic acid, hydrogen cyanide was first synthesized by C. W. Scheele in 1782.[4][5] In 1811 J. L. Gay-Lussac was able to prepare the very toxic and volatile pure acid.[6] Around 1832 benzonitrile, the nitrile of benzoic acid, was prepared by Friedrich Wöhler and Justus von Liebig, but due to minimal yield of the synthesis neither physical nor chemical properties were determined nor a structure suggested. In 1834 Théophile-Jules Pelouze synthesized propionitrile, suggesting it to be an ether of propionic alcohol and hydrocyanic acid.[7] The synthesis of benzonitrile by Hermann Fehling in 1844 by heating ammonium benzoate was the first method yielding enough of the substance for chemical research. Fehling determined the structure by comparing his results to the already known synthesis of hydrogen cyanide by heating ammonium formate. He coined the name "nitrile" for the newfound substance, which became the name for this group of compounds.[8]
Synthesis
[edit]Industrially, the main methods for producing nitriles are ammoxidation and hydrocyanation. Both routes are green in the sense that they do not generate stoichiometric amounts of salts.
Ammoxidation
[edit]In ammoxidation, a hydrocarbon is partially oxidized in the presence of ammonia. This conversion is practiced on a large scale for acrylonitrile:[9]
- CH3CH=CH2 + 3/2 O2 + NH3 → N≡CCH=CH2 + 3 H2O
In the production of acrylonitrile, a side product is acetonitrile. On an industrial scale, several derivatives of benzonitrile, phthalonitrile, as well as Isobutyronitrile are prepared by ammoxidation. The process is catalysed by metal oxides and is assumed to proceed via the imine.
Hydrocyanation
[edit]Hydrocyanation is an industrial method for producing nitriles from hydrogen cyanide and alkenes. The process requires homogeneous catalysts. An example of hydrocyanation is the production of adiponitrile, a precursor to nylon-6,6 from 1,3-butadiene:
- CH2=CH−CH=CH2 + 2 HC≡N → NC(CH2)4C≡N
From organic halides and cyanide salts
[edit]Two salt metathesis reactions are popular for laboratory scale reactions. In the Kolbe nitrile synthesis, alkyl halides undergo nucleophilic aliphatic substitution with alkali metal cyanides. Aryl nitriles are prepared in the Rosenmund-von Braun synthesis.
In general, metal cyanides combine with alkyl halides to give a mixture of the nitrile and the isonitrile, although appropriate choice of counterion and temperature can minimize the latter. An alkyl sulfate obviates the problem entirely, particularly in nonaqueous conditions (the Pelouze synthesis).[5]
Cyanohydrins
[edit]
The cyanohydrins are a special class of nitriles. Classically they result from the addition of alkali metal cyanides to aldehydes in the cyanohydrin reaction. Because of the polarity of the organic carbonyl, this reaction requires no catalyst, unlike the hydrocyanation of alkenes. O-Silyl cyanohydrins are generated by the addition trimethylsilyl cyanide in the presence of a catalyst (silylcyanation). Cyanohydrins are also prepared by transcyanohydrin reactions starting, for example, with acetone cyanohydrin as a source of HCN.[10]
Dehydration of amides
[edit]Nitriles can be prepared by the dehydration of primary amides. Common reagents for this include phosphorus pentoxide (P2O5)[11] and thionyl chloride (SOCl2).[12] In a related dehydration, secondary amides give nitriles by the von Braun amide degradation. In this case, one C-N bond is cleaved.
Oxidation of primary amines
[edit]Numerous traditional methods exist for nitrile preparation by amine oxidation.[13] Common methods include the use of potassium persulfate,[14] Trichloroisocyanuric acid,[15] or anodic electrosynthesis.[16] In addition, several selective methods have been developed in the last decades for electrochemical processes.[17]
From aldehydes and oximes
[edit]The conversion of aldehydes to nitriles via aldoximes is a popular laboratory route. Aldehydes react readily with hydroxylamine salts, sometimes at temperatures as low as ambient, to give aldoximes. These can be dehydrated to nitriles by simple heating,[18] although a wide range of reagents may assist with this, including triethylamine/sulfur dioxide, zeolites, or sulfuryl chloride. The related hydroxylamine-O-sulfonic acid reacts similarly.[19]
One-pot synthesis from aldehyde (Amberlyst is an acidic ion-exchange resin.)
In specialised cases the Van Leusen reaction can be used. Biocatalysts such as aliphatic aldoxime dehydratase are also effective.
Sandmeyer reaction
[edit]Aromatic nitriles are often prepared in the laboratory from the aniline via diazonium compounds. This is the Sandmeyer reaction. It requires transition metal cyanides.[20]
- ArN+2 + CuC≡N → ArC≡N + N2 + Cu+
Other methods
[edit]- A commercial source for the cyanide group is diethylaluminum cyanide Et2AlCN which can be prepared from triethylaluminium and HCN.[21] It has been used in nucleophilic addition to ketones.[22] For an example of its use see: Kuwajima Taxol total synthesis
- Cyanide ions facilitate the coupling of dibromides. Reaction of α,α′-dibromoadipic acid with sodium cyanide in ethanol yields the cyano cyclobutane:[23]
- Aromatic nitriles can be prepared from base hydrolysis of trichloromethyl aryl ketimines (RC(CCl3)=NH) in the Houben-Fischer synthesis[24]
- α-Amino acids form nitriles and carbon dioxide via various means of oxidative decarboxylation.[25][26] Henry Drysdale Dakin discovered this oxidation in 1916.[27]
- From aryl carboxylic acids (Letts nitrile synthesis)
Reactions
[edit]Nitrile groups in organic compounds can undergo a variety of reactions depending on the reactants or conditions. A nitrile group can be hydrolyzed, reduced, or ejected from a molecule as a cyanide ion.
Hydrolysis
[edit]The hydrolysis of nitriles RCN proceeds in the distinct steps under acid or base treatment to first give carboxamides RC(O)NH2 and then carboxylic acids RC(O)OH. The hydrolysis of nitriles to carboxylic acids is efficient. In acid or base, the balanced equations are as follows:
- RC≡N + 2 H2O + HCl → RC(O)OH + NH4Cl
- RC≡N + H2O + NaOH → RC(O)ONa + NH3
Strictly speaking, these reactions are mediated (as opposed to catalyzed) by acid or base, since one equivalent of the acid or base is consumed to form the ammonium or carboxylate salt, respectively.
Kinetic studies show that the second-order rate constant for hydroxide-ion catalyzed hydrolysis of acetonitrile to acetamide is 1.6×10−6 M−1 s−1, which is slower than the hydrolysis of the amide to the carboxylate (7.4×10−5 M−1 s−1). Thus, the base hydrolysis route will afford the carboxylate (or the amide contaminated with the carboxylate). On the other hand, the acid catalyzed reactions requires a careful control of the temperature and of the ratio of reagents in order to avoid the formation of polymers, which is promoted by the exothermic character of the hydrolysis.[28] The classical procedure to convert a nitrile to the corresponding primary amide calls for adding the nitrile to cold concentrated sulfuric acid.[29] The further conversion to the carboxylic acid is disfavored by the low temperature and low concentration of water.
- RC≡N + H2O → RC(O)NH2
Two families of enzymes catalyze the hydrolysis of nitriles. Nitrilases hydrolyze nitriles to carboxylic acids:
- RC≡N + 2 H2O → RC(O)OH + NH3
Nitrile hydratases are metalloenzymes that hydrolyze nitriles to amides.
- RC≡N + H2O → RC(O)NH2
These enzymes are used commercially to produce acrylamide.
The "anhydrous hydration" of nitriles to amides has been demonstrated using an oxime as water source:[30]
- RC≡N + R'C(H)=NOH → RC(O)NH2 + R'C≡N
Reduction
[edit]Nitriles are susceptible to hydrogenation over diverse metal catalysts. The reaction can afford either the primary amine (RCH2NH2) or the tertiary amine ((RCH2)3N), depending on conditions.[31] In conventional organic reductions, nitrile is reduced by treatment with lithium aluminium hydride to the amine. Reduction to the imine followed by hydrolysis to the aldehyde takes place in the Stephen aldehyde synthesis, which uses stannous chloride in acid.
Deprotonation
[edit]Alkyl nitriles are sufficiently acidic to undergo deprotonation of the C-H bond adjacent to the C≡N group.[32][33] Strong bases are required, such as lithium diisopropylamide and butyl lithium. The product is referred to as a nitrile anion. These carbanions alkylate a wide variety of electrophiles. Key to the exceptional nucleophilicity is the small steric demand of the C≡N unit combined with its inductive stabilization. These features make nitriles ideal for creating new carbon-carbon bonds in sterically demanding environments.
Nucleophiles
[edit]The carbon center of a nitrile is electrophilic, hence it is susceptible to nucleophilic addition reactions:
- with an organozinc compound in the Blaise reaction
- with alcohols in the Pinner reaction.
- with amines, e.g. the reaction of the amine sarcosine with cyanamide yields creatine[34]
- with arenes to form ketones in the Houben–Hoesch reaction via an imine intermediate.
- with Grignard reagents to form primary ketimines in the Moureau-Mignonac ketimine synthesis.[35] While not a classical Grignard reaction, it may be considered one under broader modern definitions.
Miscellaneous methods and compounds
[edit]- In reductive decyanation the nitrile group is replaced by a proton.[36] Decyanations can be accomplished by dissolving metal reduction (e.g. HMPA and potassium metal in tert-butanol) or by fusion of a nitrile in KOH.[37] Similarly, α-aminonitriles can be decyanated with other reducing agents such as lithium aluminium hydride.[36]
- In the so-called Franchimont Reaction (developed by the Belgian doctoral student Antoine Paul Nicolas Franchimont (1844-1919) in 1872), an α-cyanocarboxylic acid heated in acid hydrolyzes and decarboxylates to a dimer.[38]
- Nitriles self-react in presence of base in the Thorpe reaction in a nucleophilic addition
- In organometallic chemistry nitriles are known to add to alkynes in carbocyanation:[39]
Complexation
[edit]Nitriles are precursors to transition metal nitrile complexes, which are reagents and catalysts. Examples include tetrakis(acetonitrile)copper(I) hexafluorophosphate ([Cu(MeCN)4]+) and bis(benzonitrile)palladium dichloride (PdCl2(PhCN)2).[40]
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Nitrile derivatives
[edit]Organic cyanamides
[edit]Cyanamides are N-cyano compounds with general structure R1R2N−C≡N and related to the parent cyanamide.[41]
Nitrile oxides
[edit]Nitrile oxides have the chemical formula RCNO. Their general structure is R−C≡N+−O−. The R stands for any group (typically organyl, e.g., acetonitrile oxide CH3−C≡N+−O−, hydrogen in the case of fulminic acid H−C≡N+−O−, or halogen (e.g., chlorine fulminate Cl−C≡N+−O−).[42]: 1187–1192
Nitrile oxides are quite different from nitriles and do not arise from direct oxidation of the latter.[43] Instead, they can be synthesised by nitroalkane dehydration, oxime dehydrogenation,[44]: 934–936 or halooxime elimination in base.[45] They are highly reactive in 1,3-dipolar cycloadditions,[42]: 1187–1192 such as to isoxazoles,[44]: 1201–1202 and undergo type 1 dyotropic rearrangement to isocyanates.[42]: 1700
The heavier nitrile sulfides are extremely reactive and rare, but temporarily form during the thermolysis of oxathiazolones. They react similarly to nitrile oxides.[46]
Occurrence and applications
[edit]Nitriles occur naturally in a diverse set of plant and animal sources. Over 120 naturally occurring nitriles have been isolated from terrestrial and marine sources. Nitriles are commonly encountered in fruit pits, especially almonds, and during cooking of Brassica crops (such as cabbage, Brussels sprouts, and cauliflower), which release nitriles through hydrolysis. Mandelonitrile, a cyanohydrin produced by ingesting almonds or some fruit pits, releases hydrogen cyanide and is responsible for the toxicity of cyanogenic glycosides.[47]
Over 30 nitrile-containing pharmaceuticals are currently marketed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. The types of pharmaceuticals containing nitriles are diverse, from vildagliptin, an antidiabetic drug, to anastrozole, which is the gold standard in treating breast cancer. In many instances the nitrile mimics functionality present in substrates for enzymes, whereas in other cases the nitrile increases water solubility or decreases susceptibility to oxidative metabolism in the liver.[48] The nitrile functional group is found in several drugs.
-
-
Structure of citalopram, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) class -
Structure of cyamemazine, an antipsychotic drug -
Structure of fadrozole, an aromatase inhibitor for the treatment of breast cancer -
Structure of letrozole, an oral nonsteroidal aromatase inhibitor for the treatment of certain breast cancers
See also
[edit]- Protonated nitriles: Nitrilium
- Deprotonated nitriles: Nitrile anion
- Cyanocarbon
- Nitrile ylide
References
[edit]- ^ IUPAC Gold Book nitriles
- ^ NCBI-MeSH Nitriles
- ^ Karakida, Ken-ichi; Fukuyama, Tsutomu; Kuchitsu, Kozo (1974). "Molecular Structures of Hydrogen Cyanide and Acetonitrile as Studied by Gas Electron Diffraction". Bulletin of the Chemical Society of Japan. 47 (2): 299–304. doi:10.1246/bcsj.47.299.
- ^ See:
- Carl W. Scheele (1782) "Försök, beträffande det färgande ämnet uti Berlinerblå" (Experiment concerning the colored substance in Berlin blue), Kungliga Svenska Vetenskapsakademiens handlingar (Royal Swedish Academy of Science's Proceedings), 3: 264–275 (in Swedish).
- Reprinted in Latin as: "De materia tingente caerulei berolinensis" in: Carl Wilhelm Scheele with Ernst Benjamin Gottlieb Hebenstreit (ed.) and Gottfried Heinrich Schäfer (trans.), Opuscula Chemica et Physica (Leipzig ("Lipsiae"), (Germany): Johann Godfried Müller, 1789), vol. 2, pages 148–174.
- ^ a b David T. Mowry (1948). "The Preparation of Nitriles". Chemical Reviews. 42 (2): 189–283. doi:10.1021/cr60132a001. PMID 18914000.
- ^ Gay-Lussac produced pure, liquified hydrogen cyanide in: Gay-Lussac, J (1811). ""Note sur l'acide prussique" (Note on prussic acid)". Annales de chimie. 44: 128–133.
- ^ J. Pelouze (1834). "Notiz über einen neuen Cyanäther" [Note on a new cyano-ether]. Annalen der Pharmacie. 10 (3): 249. doi:10.1002/jlac.18340100302.
- ^ Hermann Fehling (1844). "Ueber die Zersetzung des benzoësauren Ammoniaks durch die Wärme (On the decomposition of ammonium benzoate by heat)". Annalen der Chemie und Pharmacie. 49 (1): 91–97. doi:10.1002/jlac.18440490106. On page 96, Fehling writes: "Da Laurent den von ihm entdeckten Körper schon Nitrobenzoyl genannt hat, auch schon ein Azobenzoyl existirt, so könnte man den aus benzoësaurem Ammoniak entstehenden Körper vielleicht Benzonitril nennen." (Since Laurent named the substance that was discovered by him "nitrobenzoyl" – also an "azobenzoyl" already exists – so one could name the substance that originates from ammonium benzoate perhaps "benzonitril".)
- ^ Pollak, Peter; Romeder, Gérard; Hagedorn, Ferdinand; Gelbke, Heinz-Peter (2000). "Nitriles". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a17_363. ISBN 3527306730.
- ^ Gregory, Robert J. H. (1999). "Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications". Chemical Reviews. 99 (12): 3649–3682. doi:10.1021/cr9902906. PMID 11849033.
- ^ "ISOBUTYRONITRILE". Organic Syntheses. 25: 61. 1945. doi:10.15227/orgsyn.025.0061.
- ^ "2-ETHYLHEXANONITRILE". Organic Syntheses. 32: 65. 1952. doi:10.15227/orgsyn.032.0065.
- ^ Schümperli, Martin T.; Hammond, Ceri; Hermans, Ive (2021). "Developments in the Aerobic Oxidation of Amines". ACS Catal. 2 (6): 1108–1117. doi:10.1021/cs300212q.
- ^ Yamazaki, Shigekazu; Yamazaki, Yasuyuki (1990). "Nickel-catalyzed dehydrogenation of amines to nitriles". Bulletin of the Chemical Society of Japan. 63 (1): 301–303. doi:10.1246/bcsj.63.301.
- ^ Chen, Fen-Er; Kuang, Yun-Yan; Hui-Fang, Dai; Lu, Liang (2003). "A Selective and Mild Oxidation of Primary Amines to Nitriles with Trichloroisocyanuric Acid". Synthesis. 17 (17): 2629–2631. doi:10.1055/s-2003-42431.
- ^ Schäfer, H. J.; Feldhues, U. (1982). "Oxidation of Primary Aliphatic Amines to Nitriles at the Nickel Hydroxide Electrode". Synthesis. 1982 (2): 145–146. doi:10.1055/s-1982-29721. S2CID 97172564.
- ^ Xu, Zhining; Kovács, Ervin (2024). "Beyond traditional synthesis: Electrochemical approaches to amine oxidation for nitriles and imines". ACS Org Inorg Au. 4 (5): 471–484. doi:10.1021/acsorginorgau.4c00025. PMC 11450732.
- ^ Chill, Samuel T.; Mebane, Robert C. (18 September 2009). "A Facile One-Pot Conversion of Aldehydes into Nitriles". Synthetic Communications. 39 (20): 3601–3606. doi:10.1080/00397910902788174. S2CID 97591561.
- ^ C. Fizet; J. Streith (1974). "Hydroxylamine-O-sulfonic acid: A convenient reagent for the oxidative conversion of aldehydes into nitriles". Tetrahedron Lett. (in German). 15 (36): 3187–3188. doi:10.1016/S0040-4039(01)91857-X.
- ^ "o-Tolunitrile and p-Tolunitrile" H. T. Clarke and R. R. Read Org. Synth. 1941, Coll. Vol. 1, 514.
- ^ W. Nagata and M. Yoshioka (1988). "Diethylaluminum cyanide". Organic Syntheses; Collected Volumes, vol. 6, p. 436.
- ^ W. Nagata, M. Yoshioka, and M. Murakami (1988). "Preparation of cyano compounds using alkylaluminum intermediates: 1-cyano-6-methoxy-3,4-dihydronaphthalene". Organic Syntheses
{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 6, p. 307. - ^ Reynold C. Fuson; Oscar R. Kreimeier & Gilbert L. Nimmo (1930). "Ring Closures in the Cyclobutane Series. II. Cyclization Of α,α′-Dibromo-Adipic Esters". J. Am. Chem. Soc. 52 (10): 4074–4076. doi:10.1021/ja01373a046.
- ^ J. Houben, Walter Fischer (1930) "Über eine neue Methode zur Darstellung cyclischer Nitrile durch katalytischen Abbau (I. Mitteil.)," Berichte der deutschen chemischen Gesellschaft (A and B Series) 63 (9): 2464 – 2472. doi:10.1002/cber.19300630920
- ^ Hiegel, Gene; Lewis, Justin; Bae, Jason (2004). "Conversion of α-Amino Acids into Nitriles by Oxidative Decarboxylation with Trichloroisocyanuric Acid". Synthetic Communications. 34 (19): 3449–3453. doi:10.1081/SCC-200030958. S2CID 52208189.
- ^ Hampson, N; Lee, J; MacDonald, K (1972). "The oxidation of amino compounds at anodic silver". Electrochimica Acta. 17 (5): 921–955. doi:10.1016/0013-4686(72)90014-X.
- ^ Dakin, Henry Drysdale (1916). "The Oxidation of Amino-Acids to Cyanides". Biochemical Journal. 10 (2): 319–323. doi:10.1042/bj0100319. PMC 1258710. PMID 16742643.
- ^ Kukushkin, V. Yu.; Pombeiro, A. J. L. (2005). "Metal-mediated and metal-catalyzed hydrolysis of nitriles". Inorg. Chim. Acta. 358: 1–21. doi:10.1016/j.ica.2004.04.029.
- ^ Abbas, Khamis A. (1 January 2008). "Substituent Effects on the Hydrolysis of p-Substituted Benzonitriles in Sulfuric Acid Solutions at (25.0± 0.1) °C". Zeitschrift für Naturforschung A. 63 (9): 603–608. Bibcode:2008ZNatA..63..603A. doi:10.1515/zna-2008-0912. ISSN 1865-7109.
- ^ Dahye Kang; Jinwoo Lee; Hee-Yoon Lee (2012). "Anhydrous Hydration of Nitriles to Amides: p-Carbomethoxybenzamide". Organic Syntheses. 89: 66. doi:10.15227/orgsyn.089.0066.
- ^ Barrault, J.; Pouilloux, Y. (1997). "Catalytic Amination Reactions: Synthesis of fatty amines. Selectivity control in presence of multifunctional catalysts". Catalysis Today. 1997 (2): 137–153. doi:10.1016/S0920-5861(97)00006-0.
- ^ Arseniyadis, Siméon; Kyler, Keith S.; Watt, David S. (1984). "Addition and Substitution Reactions of Nitrile-Stabilized Carbanions". Organic Reactions. pp. 1–364. doi:10.1002/0471264180.or031.01. ISBN 978-0-471-26418-7.
- ^ Yang, Xun; Fleming, Fraser F. (2017). "C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity". Accounts of Chemical Research. 50 (10): 2556–2568. doi:10.1021/acs.accounts.7b00329. PMID 28930437.
- ^ Smith, Andri L.; Tan, Paula (2006). "Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment". J. Chem. Educ. 83 (11): 1654. Bibcode:2006JChEd..83.1654S. doi:10.1021/ed083p1654.
- ^ "Moureau-Mignonac Ketimine Synthesis". Comprehensive Organic Name Reactions and Reagents. Hoboken, NJ, USA: John Wiley & Sons, Inc. 15 September 2010. pp. 1988–1990. doi:10.1002/9780470638859.conrr446. ISBN 9780470638859.
- ^ a b The reductive decyanation reaction: chemical methods and synthetic applications Jean-Marc Mattalia, Caroline Marchi-Delapierre, Hassan Hazimeh, and Michel Chanon Arkivoc (AL-1755FR) pp. 90–118 2006 Article[permanent dead link]
- ^ Berkoff, Charles E.; Rivard, Donald E.; Kirkpatrick, David; Ives, Jeffrey L. (1980). "The Reductive Decyanation of Nitriles by Alkali Fusion". Synthetic Communications. 10 (12): 939–945. doi:10.1080/00397918008061855.
- ^ Franchimont, Antoine Paul Nicholas (1872). "Ueber die Dibenzyldicarbonsäure" [On 2,3-diphenylsuccinic acid]. Berichte der Deutschen Chemischen Gesellschaft. 5 (2): 1048–1050. doi:10.1002/cber.187200502138.
- ^ Yoshiaki Nakao; Akira Yada; Shiro Ebata & Tamejiro Hiyama (2007). "A Dramatic Effect of Lewis-Acid Catalysts on Nickel-Catalyzed Carbocyanation of Alkynes". J. Am. Chem. Soc. (Communication). 129 (9): 2428–2429. doi:10.1021/ja067364x. PMID 17295484.
- ^ Rach, S. F.; Kühn, F. E. (2009). "Nitrile Ligated Transition Metal Complexes with Weakly Coordinating Counteranions and Their Catalytic Applications". Chemical Reviews. 109 (5): 2061–2080. doi:10.1021/cr800270h. PMID 19326858.
- ^ March, Jerry (1992). Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (4th ed.). New York: Wiley. p. 436–7. ISBN 0-471-60180-2.
- ^ a b c Smith, Michael B.; March, Jerry (2007). March's Advanced Organic Chemistry (6th ed.). John Wiley & Sons. ISBN 978-0-471-72091-1.
- ^ Grundmann, Ch. (1970). "Nitrile oxides". In Rappoport, Zvi (ed.). The Chemistry of the Cyano Group. PATai's Chemistry of Functional Groups. p. 794. doi:10.1002/9780470771242.ch14. ISBN 978-0-471-70913-8.
- ^ a b Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. ISBN 978-0-19-850346-0.
- ^ Hagedorn, Alfred A.; Miller, Bryan J.; Nagy, Jon O. (1980) [12 Oct 1979]. "Direct synthesis of the antitumor agent erythro-α‑amino-3‑bromo-4,5‑dihydrooxazole-5‑acetic acid". Tetrahedron Letters. 21. Great Britain: Pergamon: 229–230. doi:10.1016/S0040-4039(00)71175-0, alluding to a large-scale modification later detailed in Vyas, D. M.; Chiang, Y.; Doyle, T. W. (1984). "A short, efficient total synthesis of (±) acivicin and (±) bromo-acivicin". Tetrahedron Letters. 25 (5). Great Britain: Pergamon. fn. 10. doi:10.1016/S0040-4039(00)99918-0.
- ^ Argyropoulos, Nikolaos G. (1996). "1,4-Oxa/thia-2-azoles". In Katritzky, Alan R.; Rees, Charles W.; Scriven, Eric F. V. (eds.). Comprehensive Heterocyclic Chemistry. Vol. 4: Five-membered rings with more than two heteroatoms and fused carbocyclic derivatives. pp. 506–507. doi:10.1016/B978-008096518-5.00092-7. ISBN 978-0-08-096518-5.
- ^ Natural Product Reports Issue 5, 1999 Nitrile-containing natural products
- ^ Fleming, Fraser F.; Yao, Lihua; Ravikumar, P. C.; Funk, Lee; Shook, Brian C. (November 2010). "Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore". J Med Chem. 53 (22): 7902–17. doi:10.1021/jm100762r. PMC 2988972. PMID 20804202.
External links
[edit]- IUPAC, Compendium of Chemical Terminology, 5th ed. (the "Gold Book") (2025). Online version: (2006–) "nitrile". doi:10.1351/goldbook.N04151
- IUPAC, Compendium of Chemical Terminology, 5th ed. (the "Gold Book") (2025). Online version: (2006–) "cyanide". doi:10.1351/goldbook.C01486
Nitrile
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A nitrile is an organic compound characterized by the presence of a cyano functional group, consisting of a carbon atom triple-bonded to a nitrogen atom (-C≡N).[1] This group imparts distinctive chemical properties, making nitriles versatile intermediates in organic synthesis and key components in various industrial materials.[1]
The structure of a nitrile features a linear arrangement due to sp-hybridization of both the carbon and nitrogen atoms, resulting in a bond angle of 180° and a highly polarized triple bond.[1] The nitrogen atom bears a lone pair in an sp hybrid orbital, contributing to the group's electrophilic character at the carbon end, analogous to carbonyl compounds.[1] Nitriles exhibit higher boiling points than hydrocarbons of similar molecular weight owing to their polarity and dipole-dipole interactions, and lower nitriles are soluble in water due to their polarity, while solubility decreases with increasing chain length; they are generally soluble in organic solvents.[1] In terms of basicity, nitriles are weaker bases than amines because of the 50% s-character in the nitrogen's lone pair orbital.[1]
Nomenclature for nitriles follows IUPAC conventions, where the suffix "-nitrile" is added to the name of the parent hydrocarbon chain, including the carbon of the cyano group in the chain length; alternatively, they may be named as alkyl cyanides or using the "cyano-" prefix for substituents.[2] For example, CH₃CH₂CH₂CN is named butanenitrile, reflecting a four-carbon chain.[2]
Nitriles are prepared through several methods, including the nucleophilic substitution (Sₙ2) reaction of alkyl halides with cyanide ions (e.g., NaCN), dehydration of primary amides using reagents like thionyl chloride (SOCl₂) or phosphorus pentoxide (P₂O₅), and formation of cyanohydrins from aldehydes or ketones.[1] Their reactivity stems from the electrophilic carbon, enabling hydrolysis under acidic or basic conditions to yield carboxylic acids (often via amide intermediates), reduction with lithium aluminum hydride (LiAlH₄) to primary amines, partial reduction with diisobutylaluminum hydride (DIBALH) to aldehydes, and addition of Grignard reagents to form ketones after hydrolysis.[1]
Beyond synthesis, nitriles play crucial roles in industry and medicine; for instance, acrylonitrile is a monomer for producing nitrile butadiene rubber (NBR), valued for its oil and chemical resistance in applications like automotive seals, hoses, and protective gloves.[3] Certain nitrile-containing compounds, such as cyamemazine and citalopram, are used in pharmaceuticals for their therapeutic effects.[1]
This method provides a straightforward route to N-monosubstituted cyanamides in good yields. Organic cyanamides exhibit greater basicity than simple nitriles due to the amine-like NH group, which allows for protonation or deprotonation more readily than the weakly basic nitrogen in R-C≡N. In infrared spectroscopy, they display a characteristic C≡N stretching absorption in the 2100-2200 cm⁻¹ region, slightly broader and lower in frequency compared to typical nitriles owing to the adjacent nitrogen atom. A key reaction of organic cyanamides is acid- or base-catalyzed hydrolysis, which converts them to N-monosubstituted ureas through addition of water across the cumulative bonds:
This transformation is valuable for urea synthesis. Additionally, organic cyanamides serve as crosslinkers in polymer chemistry, where their reactivity enables the formation of networked structures in materials like polyurethanes and resins. In applications, organic cyanamides act as intermediates in the synthesis of various agrochemicals and pharmaceuticals.
Fundamentals
Definition and Nomenclature
Nitriles are a class of organic compounds characterized by the presence of a cyano functional group consisting of a carbon-nitrogen triple bond, represented by the general formula R–C≡N, where R denotes an organic substituent such as an alkyl, aryl, or other hydrocarbon group.[4] This distinguishes nitriles from inorganic cyanides, such as hydrogen cyanide (HCN) or metal cyanides, which lack an organic R group and are typically simple salts or acids rather than carbon-based derivatives.[5] In IUPAC nomenclature, nitriles are primarily named using the substitutive approach, where the parent chain is selected to include the carbon atom of the –C≡N group, and the suffix "-nitrile" (or "-carbonitrile" for cyclic or more complex structures) is appended to the name of the corresponding alkane, dropping the final "e". For instance, the compound with the formula CH₃–C≡N is named ethanenitrile, while CH₃CH₂CH₂–C≡N is butanenitrile, with the chain length counting the cyano carbon as position 1.[6] When the –C≡N group is a substituent rather than the principal function, it is denoted by the prefix "cyano-".[6] Nitriles hold a high seniority order among functional groups in IUPAC naming, allowing them to be expressed as the suffix when serving as the principal characteristic group in a compound, superseding lower-priority functions like halides or hydrocarbons.[6] Common or retained names are also employed for simple nitriles, such as acetonitrile for ethanenitrile (CH₃CN).[7] The term "nitrile" itself derives from French "nitrile" and German "Nitril", borrowings linked to "nitre" through historical associations with cyanide compounds produced from saltpeter (potassium nitrate).[8]Structure and Bonding
The nitrile functional group is characterized by the linear arrangement R–C≡N, where the carbon and nitrogen atoms exhibit sp hybridization, leading to a bond angle of 180° at the carbon atom. This hybridization arises from the overlap of one s and one p orbital on each atom, forming two sp hybrid orbitals, while the remaining two p orbitals on carbon and nitrogen contribute to the pi bonding.[9] The triple bond in the -C≡N moiety comprises one σ bond, formed by end-to-end overlap of sp hybrid orbitals from carbon and nitrogen, and two π bonds, resulting from the sideways overlap of unhybridized p orbitals. The C≡N bond length is approximately 116 pm in simple nitriles like acetonitrile, while the C–R bond adopts a typical single-bond length, such as 147 pm in CH₃CN. The structural formula can be represented as: \ce{R - ^{sp}C#N^{sp}} where the superscripts indicate the hybridization states.[10][11] Due to the electronegativity difference between carbon (2.55) and nitrogen (3.04), the C≡N bond is polar, with the nitrogen bearing a partial negative charge and the carbon a partial positive charge, resulting in a dipole moment of approximately 3.9 D for acetonitrile.[12] Simple aliphatic nitriles show minimal resonance stabilization, as the triple bond limits delocalization without adjacent π systems. In contrast, the cyano group in benzonitrile demonstrates strong electron-withdrawing inductive and resonance effects, quantified by a Hammett substituent constant σ_p = 0.66.[13]Physical and Chemical Properties
Nitriles exhibit higher boiling points than hydrocarbons of comparable molecular weight due to the polarity of the cyano group, which induces dipole-dipole interactions. For instance, acetonitrile (CH₃CN, molecular weight 41 g/mol) has a boiling point of 82°C, whereas propane (C₃H₈, similar molecular weight) boils at -42°C.[7][14] The solubility of nitriles in water decreases with increasing alkyl chain length, as the polar cyano group enables hydrogen bonding with water in shorter-chain compounds, while longer hydrophobic chains reduce this affinity. Acetonitrile is fully miscible with water, propanenitrile dissolves to about 11 g per 100 cm³ at 20°C, and higher homologs like hexanenitrile show limited solubility (around 0.25 g per 100 cm³ at 25°C).[7][15][16] Densities of nitriles typically range from 0.8 to 1.0 g/cm³ at 20°C, reflecting their compact structure and moderate polarity; for example, acetonitrile has a density of 0.786 g/cm³, while benzonitrile is denser at 1.01 g/cm³.[7][17] In infrared (IR) spectroscopy, nitriles display a characteristic sharp and intense absorption band for the C≡N stretch in the range of 2200-2260 cm⁻¹, with saturated aliphatic nitriles appearing near 2250 cm⁻¹ and aromatic ones slightly lower around 2230 cm⁻¹.[18][18] Nuclear magnetic resonance (NMR) spectroscopy provides key identifiers for nitriles: the cyano carbon in ¹³C NMR resonates at 110-120 ppm, downfield from typical alkane carbons but upfield relative to carbonyls. Protons alpha to the cyano group in ¹H NMR are deshielded, appearing in the 2-3 ppm region due to the electron-withdrawing effect of the nitrile.[18][18] Nitriles demonstrate good thermal stability, remaining intact up to approximately 200°C under neutral conditions, as evidenced by their use in high-temperature reactions without decomposition. They are generally inert to many oxidizing and reducing agents but undergo hydrolysis to carboxylic acids or amides under acidic or basic catalysis.[19][1] Aliphatic nitriles pose toxicity risks primarily through metabolic conversion in the liver to hydrogen cyanide (HCN) via cytochrome P450 oxidation, leading to cyanide poisoning symptoms. For example, the oral LD₅₀ of acetonitrile in rats is 2460 mg/kg, indicating moderate acute toxicity.[20][21]Historical Development
Discovery
The discovery of nitriles traces back to the late 18th century with the identification of hydrogen cyanide (HCN), the simplest nitrile and a key precursor in cyanide chemistry. In 1782, Swedish chemist Carl Wilhelm Scheele first prepared HCN by distilling Prussian blue (ferric ferrocyanide) with sulfuric acid, yielding a colorless, toxic gas that he described as having acidic properties.[22] This compound was soon recognized as prussic acid due to its derivation from the Prussian blue pigment, a deep blue ferrocyanide salt widely used in dyes and paints since its invention in the early 18th century.[22] Early cyanide chemistry, centered on such ferrocyanide compounds, played a foundational role in pigment production for textiles and art, laying groundwork for broader applications in industrial processes.[23] HCN's presence in natural sources further highlighted its significance in early chemical investigations. In the 1830s, German chemists Justus von Liebig and Friedrich Wöhler, while studying the essential oil from bitter almonds, demonstrated that amygdalin—a glycoside in the kernels—hydrolyzes to yield glucose, benzaldehyde, and prussic acid (HCN), accounting for the characteristic bitter almond odor associated with cyanide release upon tissue damage. Their work not only isolated pure prussic acid from this natural decomposition but also advanced understanding of cyanogenic compounds in plants, linking HCN to both toxicity and sensory properties.[24] Building on HCN's chemistry, the first organic nitriles emerged in the early 19th century through systematic organic synthesis. In 1832, Liebig and Wöhler achieved the inaugural preparation of benzonitrile (C6H5CN), the nitrile derivative of benzoic acid, via dehydration of benzamide during their benzoyl radical studies—this marked the first documented synthesis of an organic nitrile and exemplified the radical theory's application to carbon-nitrogen functionalities.[25] Shortly thereafter, in 1847, French chemist Jean-Baptiste Dumas isolated acetonitrile (CH3CN), the simplest aliphatic organic nitrile, as a byproduct during the distillation of acetic acid derivatives with cyanides, further expanding the class beyond aromatic examples.[26] These isolations underscored nitriles' structural relation to HCN, with the cyano group (-C≡N) serving as a versatile functional group in emerging organic chemistry.Key Milestones
The development of industrial-scale processes for nitrile production marked significant milestones in 20th-century chemistry, transforming nitriles from laboratory curiosities into essential industrial feedstocks. In the 1940s, German chemist Walter Reppe at BASF pioneered high-pressure synthesis methods, including the addition of hydrogen cyanide to acetylene to produce acrylonitrile, which supported wartime production of synthetic rubber and fibers.[27] This approach laid foundational techniques for handling reactive gases under pressure, influencing subsequent catalytic innovations.[28] A pivotal breakthrough occurred in the late 1950s with the invention of the ammoxidation process at Standard Oil of Ohio (SOHIO). In 1957, researchers discovered that propylene could be directly converted to acrylonitrile using ammonia and air over a bismuth phosphomolybdate catalyst, achieving yields up to 50% in initial experiments and enabling commercial operation by 1960.[29] This SOHIO process, later honored as a National Historic Chemical Landmark by the American Chemical Society, reduced production costs by over 50% compared to prior acetylene-based methods and scaled global acrylonitrile output to millions of tons annually, fueling the growth of acrylic fibers, ABS plastics, and carbon fibers.[30] Parallel advances in synthetic routes for polyamide precursors highlighted nitriles' role in materials science. In the early 1970s, DuPont researchers, led by William C. Drinkard, developed a nickel-catalyzed hydrocyanation of 1,3-butadiene to adiponitrile, with the first commercial plant commencing production in 1971. This two-step process—initial hydrocyanation to 3- and 4-pentenenitrile followed by isomerization and second hydrocyanation—provided an economical pathway to hexamethylenediamine, the key monomer for nylon 6,6, and accounted for a significant portion of global adiponitrile capacity by the 1980s.[31] Post-2000 developments emphasized stereoselective and sustainable nitrile chemistry, building on asymmetric catalysis principles from Ryoji Noyori's 2001 Nobel Prize-winning work on chiral hydrogenation. Extensions to nitrile hydrogenation and hydrocyanation enabled enantioselective reductions, with ruthenium and iron catalysts achieving high ee values for chiral amine synthesis from nitriles by the mid-2010s.[32] Catalytic asymmetric hydrocyanation of alkenes emerged as a key area, with nickel-phosphite systems delivering up to 95% ee in intermolecular additions by 2010, facilitating access to chiral nitriles for fine chemicals.[33] In the 2020s, green synthesis trends have prioritized eco-friendly alternatives to traditional cyanation routes. Electrochemical methods, such as nickel-catalyzed electrosynthesis from alcohols and ammonia, have gained traction for producing nitriles under mild conditions without stoichiometric cyanide, aligning with sustainability goals in industrial chemistry.[34] Biocatalytic approaches using nitrilases and hydratases have also advanced, enabling selective conversions from renewable feedstocks with minimal waste.[35] A notable 21st-century milestone in applied nitrile chemistry was the approval of vildagliptin in 2007 by the European Medicines Agency. This cyanopyrrolidine-based dipeptidyl peptidase-4 inhibitor, featuring a key nitrile group that forms a reversible covalent adduct with the enzyme's serine residue, became a blockbuster antidiabetic drug, exemplifying nitriles' growing utility in targeted pharmacophores.[36]Synthesis
Ammoxidation
Ammoxidation is an industrial process for synthesizing nitriles through the catalytic partial oxidation of hydrocarbons, typically alkenes or alkanes, in the presence of ammonia and oxygen. In this reaction, a methyl or methylene group adjacent to a double bond or in an activated position is converted to a nitrile functionality, with water as the primary byproduct. The most prominent example is the production of acrylonitrile from propylene, where the reaction proceeds as follows: This process, developed in the 1950s, enables the direct incorporation of nitrogen from ammonia into the hydrocarbon framework under controlled oxidative conditions.[37][38] The mechanism of ammoxidation involves a multi-step redox pathway on the surface of metal oxide catalysts, often following a Mars-van Krevelen-type mechanism where lattice oxygen participates in the oxidation. Propylene is initially activated via abstraction of an allylic hydrogen to form a surface-bound allyl intermediate, which then interacts with adsorbed ammonia or imide species derived from NH3 and O2 to yield an imine. Subsequent dehydrogenation and oxygen-assisted elimination lead to the nitrile product, with catalyst reoxidation by gaseous O2 completing the cycle. Bismuth-molybdate catalysts, such as Bi2Mo3O12, are particularly effective due to their ability to facilitate selective C-H activation at the allylic position while minimizing over-oxidation to COx. This pathway ensures high selectivity toward the desired unsaturated nitrile, distinguishing it from simple oxidation.[37][38] Industrial ammoxidation operates at high temperatures of 400–500°C and atmospheric pressure in vapor-phase reactors, such as fluidized-bed or circulating fluidized-bed systems, using a feed mixture of hydrocarbon (5–10 vol%), ammonia (7–12 vol%), oxygen or air (5–10 vol%), and steam or inert diluents. Catalysts like multicomponent bismuth-molybdate supported on alumina (e.g., Mo-Bi/α-Al2O3) enable single-pass yields exceeding 70% for acrylonitrile, with selectivities up to 85–90% under optimized conditions. Globally, this process produces millions of tons of acrylonitrile annually—approximately 8.8 million metric tons as of 2025—making it a cornerstone for commodity nitrile synthesis and supporting downstream industries like polymers. The high yields and scalability stem from the exothermic nature of the reaction (ΔH ≈ -510 kJ/mol), which provides process heat while requiring careful temperature control to prevent hotspots and side reactions like HCN formation.[39][40]Hydrocyanation
Hydrocyanation refers to the catalytic addition of hydrogen cyanide (HCN) to unsaturated compounds, such as alkenes and alkynes, to form nitriles. This reaction is a key method for synthesizing aliphatic nitriles, particularly linear ones, and is widely employed in industrial processes due to its atom-economic nature. The general transformation for terminal alkenes proceeds with anti-Markovnikov regioselectivity, as illustrated by the equation: This addition is facilitated by transition metal catalysts, with nickel-based systems being predominant for both laboratory and commercial scales.[41] The mechanism of nickel-catalyzed hydrocyanation involves oxidative addition of HCN to a low-valent nickel species, followed by coordination of the alkene to form a π-complex. Subsequent insertion leads to a π-allyl nickel intermediate, which directs the anti-Markovnikov orientation by placing the cyanide group at the less substituted carbon. Reductive elimination then releases the nitrile product and regenerates the catalyst. A prominent industrial application is the DuPont process for adiponitrile production, which converts 1,3-butadiene to the dinitrile precursor for nylon-6,6 via sequential hydrocyanations: This overall reaction highlights the utility of hydrocyanation in polymer chemistry.[42][43] Typical conditions for these reactions utilize homogeneous nickel(0) catalysts coordinated to phosphine or phosphite ligands, such as triphenylphosphite, often in the presence of a Lewis acid promoter like zinc chloride. Reactions are conducted at temperatures of 80–120°C under moderate pressure to maintain liquid-phase conditions and ensure HCN solubility. Asymmetric hydrocyanation variants employ chiral bidentate phosphine ligands to achieve high enantioselectivity, enabling the synthesis of enantioenriched nitriles from prochiral alkenes. The scope is largely confined to unactivated or conjugated alkenes and alkynes, yielding linear aliphatic nitriles suitable for further derivatization into amines or carboxylic acids.[44][45][46]From Alkyl Halides and Cyanide
One common method for synthesizing alkyl nitriles involves the nucleophilic substitution of alkyl halides with cyanide ions, which proceeds via an SN2 mechanism. In this process, the cyanide ion (CN⁻) acts as a strong nucleophile, displacing the halide ion (X⁻) from the alkyl halide (R-X) to form the alkyl nitrile (R-CN) and the corresponding metal halide salt.[47] Primary alkyl halides are particularly suitable substrates, as they undergo clean SN2 displacement with minimal side reactions.[48] A representative example is the conversion of ethyl bromide to propanenitrile using potassium cyanide: This reaction is typically carried out with KCN or NaCN as the cyanide source in polar solvents such as ethanol or dimethyl sulfoxide (DMSO).[49] Conditions often involve heating under reflux or at elevated temperatures (60–140°C), depending on the substrate, to achieve yields of 70–93% for primary alkyl halides.[47] Secondary and tertiary alkyl halides are less effective due to steric hindrance, which favors E2 elimination to alkenes over SN2 substitution, resulting in poor nitrile yields and byproduct formation.[47] Phase-transfer catalysis, employing quaternary ammonium salts in biphasic aqueous-organic media, can enhance reaction rates and yields for challenging substrates by improving cyanide ion solubility and availability.[50]From Cyanohydrins
Nitriles can be synthesized from cyanohydrins through a two-step process involving the nucleophilic addition of hydrogen cyanide to aldehydes or ketones, followed by dehydration of the resulting α-hydroxynitrile intermediate. This route is particularly effective for producing α,β-unsaturated nitriles when starting from aldehydes with α-hydrogens, as the dehydration step involves elimination of water across the β and α positions.[51] The initial cyanohydrin formation proceeds via base-catalyzed addition of HCN to the carbonyl group, where the cyanide ion attacks the electrophilic carbon, and the oxygen is protonated to yield the α-hydroxynitrile; alternatively, enzymatic catalysis using hydroxynitrile lyases enables stereoselective synthesis under mild aqueous conditions.[52] The general reaction scheme is illustrated below for an aldehyde with an α-methylene group: Dehydration typically employs reagents such as phosphorus oxychloride (POCl3) in an inert solvent or concentrated sulfuric acid, often at elevated temperatures of 100-150°C to facilitate elimination while minimizing side reactions like cyanohydrin reversion to the carbonyl and HCN.[53][51] A key industrial application of this method is the historical production of acrylonitrile, where acetaldehyde is converted to lactonitrile (CH₃CH(OH)CN) and then dehydrated to CH₂=CHCN. This process, though largely superseded by propylene ammoxidation, provided high yields (>80%) of the unsaturated nitrile using dehydrating agents like phosphorus pentoxide.[54][55]Dehydration of Amides
The dehydration of primary amides represents a classical and widely employed route to nitriles, wherein the general transformation RCONH₂ → RCN + H₂O occurs through the action of a dehydrating agent.[56] This method is particularly effective for preparing aliphatic and aromatic nitriles, leveraging the structural similarity between amides and nitriles to facilitate straightforward water elimination.[57] Common dehydrating agents include phosphorus pentoxide (P₂O₅), thionyl chloride (SOCl₂), and p-toluenesulfonyl chloride (TsCl) in the presence of pyridine.[58] For instance, the reaction of acetamide with P₂O₅ yields acetonitrile, as depicted in the simplified equation: [56] The mechanism proceeds via initial coordination of the dehydrating agent to the carbonyl oxygen of the amide, enhancing the electrophilicity of the carbonyl carbon and promoting proton transfer from the nitrogen, followed by elimination of water to form the nitrile. With SOCl₂, this involves nucleophilic attack by the amide oxygen on sulfur, generating an intermediate chlorosulfonium species that undergoes deprotonation and loss of SO₂ and HCl.[59][60] These reactions are conducted under anhydrous conditions to prevent hydrolysis, typically at elevated temperatures of 50–200 °C depending on the reagent—for example, reflux in inert solvents for SOCl₂ or direct heating for P₂O₅.[56] High yields, often exceeding 90%, are achieved particularly with aliphatic primary amides, owing to their reduced steric hindrance and lack of conjugative stabilization that might complicate aromatic counterparts.[59] Primary amides for this process are commonly derived from carboxylic acids through conversion to acid chlorides or esters followed by ammonolysis.[57]Oxidation of Amines
The oxidation of primary amines to nitriles represents a direct and efficient synthetic route for constructing the nitrile functionality from readily available amine starting materials, particularly useful for aliphatic and benzylic systems. This transformation proceeds through the net loss of two equivalents of hydrogen and one equivalent of water, converting the RCH₂NH₂ moiety to RCN.[61] The mechanism involves successive dehydrogenation steps, beginning with the oxidation of the primary amine to an imine intermediate (RCH=NH), followed by further dehydrogenation of the imine to the nitrile (RCN). This process typically occurs via hydride or hydrogen atom transfer to the oxidant, with the imine serving as a key reactive species that tautomerizes or loses hydrogen to form the triple bond characteristic of the nitrile group.[62] Common reagents for this oxidation include manganese dioxide (MnO₂) and hypervalent iodine compounds, which enable selective conversion under mild conditions to minimize side reactions such as over-oxidation to carbonyl compounds. For instance, MnO₂ in the presence of air oxidizes primary amines to nitriles by facilitating dehydrogenation at ambient or slightly elevated temperatures, often in organic solvents like dichloromethane, with high yields for benzylic amines. Similarly, hypervalent iodine reagents such as iodosobenzene (PhIO) effect the transformation in aqueous or dichloromethane media at room temperature, proceeding through an electrophilic iodine-mediated pathway that promotes the imine-to-nitrile step efficiently for aliphatic primary amines.[63] A representative example is the oxidation of benzylamine to benzonitrile: This reaction exemplifies the selectivity achievable with mild oxidants, where aqueous or organic solvents are employed to solubilize the amine and control reactivity, often yielding the nitrile in over 80% isolated yield without significant byproduct formation.[63]Other Methods
One specialized route to aryl nitriles involves the Sandmeyer reaction variant, where aryldiazonium salts react with copper(I) cyanide to afford the corresponding aryl cyanide, displacing nitrogen gas: This method, historically significant for aromatic systems, proceeds via a radical mechanism facilitated by the copper catalyst and is particularly useful for preparing benzonitriles from anilines after diazotization.[64] Nitriles can also be synthesized from aldehydes through a two-step process involving oxime formation followed by dehydration. The aldehyde first reacts with hydroxylamine to form the aldoxime: Subsequent catalytic dehydration of the oxime yields the nitrile: This approach is versatile for both aliphatic and aromatic nitriles and can be performed under mild conditions using catalysts such as N-(p-toluenesulfonyl)imidazole or Brønsted acids, avoiding hazardous cyanides. Modern synthetic methods include palladium-catalyzed cyanation of aryl halides, which enables efficient incorporation of the cyano group into aromatic frameworks. For instance, aryl bromides react with zinc cyanide in the presence of a palladium catalyst and ligands like dppf to produce aryl nitriles: This protocol operates under mild conditions and tolerates a broad range of functional groups, making it a practical alternative to classical routes. Similarly, aryl iodides can undergo cyanation using potassium ferrocyanide as a non-toxic cyanide source: These transformations leverage the low toxicity of the cyanide precursors and have been optimized for high yields in aqueous or alcoholic media.[65] Electrochemical synthesis represents an emerging, sustainable approach to nitriles, often coupling alcohols or amines with ammonia or other nitrogen sources under mild conditions. For example, primary alcohols can be converted to nitriles via anodic oxidation on nickel electrodes in aqueous ammonia, proceeding through dehydrogenation and imine intermediates without external oxidants. This method minimizes waste and energy use, with recent advances enabling selective production of aryl and aliphatic nitriles at ambient temperature.[66] Green methodologies have addressed toxicity concerns in nitrile synthesis, notably through the use of urea as a cyanide source in photoredox-catalyzed processes post-2010. In these reactions, organic chlorides or other electrophiles react with urea under visible-light irradiation and nickel or copper catalysts, generating the cyano group via in situ formation of cyanide equivalents from urea decomposition, often coupled with CO2 reduction. This atom-economical strategy avoids free cyanide and has been applied to diverse substrates, yielding nitriles in good efficiency while producing benign byproducts like hydrogen.[67]Reactions
Hydrolysis
Hydrolysis of nitriles converts the nitrile functional group (RC≡N) into carboxylic acids (RCOOH) or amides (RCONH₂) through the addition of water under acidic or basic conditions. In acidic hydrolysis, the reaction proceeds via protonation of the nitrile nitrogen, enhancing the electrophilicity of the carbon atom and facilitating nucleophilic attack by water. The overall process yields the carboxylic acid and an ammonium salt, represented by the equation: This two-step transformation first forms an amide intermediate, which is further hydrolyzed to the acid.[1] The mechanism begins with protonation of the nitrile to form an iminium ion, followed by nucleophilic addition of water to generate a protonated hemiaminal. This intermediate undergoes proton transfer and dehydration to yield a protonated amide, which is then hydrolyzed similarly to amide hydrolysis, expelling ammonia as NH₄⁺ and forming the carboxylic acid. The amide intermediate (RCONH₂) can often be isolated by controlling reaction conditions to halt at the first stage. Specialized methods for selective hydration to amides employ acetic acid as solvent with catalysts such as mercury(II) acetate or the boron trifluoride–acetic acid complex; these are not general approaches, involve toxic reagents, and are unsuitable for routine full hydrolysis to carboxylic acids.[68][69] For instance, the hydrolysis of acetonitrile under acidic conditions follows: Acidic conditions typically employ concentrated HCl or H₂SO₄ with reflux.[70] In basic hydrolysis, hydroxide ion adds directly to the nitrile carbon, forming an imidate anion that tautomerizes to the amide anion; subsequent steps mirror acidic hydrolysis but produce ammonia (NH₃) instead of ammonium ion. The reaction equation is: The carboxylate salt (RCOO⁻) is obtained initially and requires acidification (e.g., with HCl) to isolate the free carboxylic acid. Basic conditions use aqueous NaOH or KOH under reflux. The amide intermediate is also accessible under milder basic conditions. Electron-withdrawing substituents on the R group facilitate hydrolysis by stabilizing the developing negative charge in the transition state during nucleophilic addition.[1]Reduction
The reduction of nitriles to primary amines involves the addition of four hydrogen equivalents to the carbon-nitrogen triple bond, transforming R-C≡N into R-CH₂-NH₂. This process is a cornerstone of synthetic organic chemistry for preparing amines from nitrile precursors.[1] Catalytic hydrogenation represents an efficient and scalable method for this transformation, as depicted in the general equation: Raney nickel serves as a widely used catalyst, particularly in industrial applications, where the reaction proceeds under moderate to high pressure (typically 50–100 atm) and elevated temperatures to ensure complete conversion. This approach minimizes side products and is compatible with a broad range of aromatic and aliphatic nitriles.[71][72] Stoichiometric reducing agents like lithium aluminum hydride (LiAlH₄) also achieve full reduction to primary amines. A representative example is the conversion of benzonitrile: The reaction is typically conducted in anhydrous ether solvents at 0–25°C, followed by aqueous workup to liberate the free amine. LiAlH₄ provides hydride ions that add sequentially to the nitrile, ensuring high yields for sensitive substrates.[73] The mechanism of nitrile reduction, whether catalytic or stoichiometric, proceeds via a key imine intermediate. Initial nucleophilic addition of a hydride (or hydrogen equivalent) to the electrophilic carbon of the nitrile forms an imine anion, which is protonated to yield an aldimine (R-CH=NH). Subsequent reduction of this imine delivers the final primary amine through another hydride addition and protonation step. This stepwise process highlights the role of the triple bond in facilitating controlled hydrogen incorporation.[74][1] For selective partial reduction to aldehydes, milder agents like diisobutylaluminum hydride (DIBAL-H) are employed, which coordinate to the nitrogen and deliver only two hydride equivalents, forming a stable imine intermediate that hydrolyzes to R-CHO upon aqueous workup. This method avoids over-reduction to amines by using controlled stoichiometry (typically 1–1.5 equivalents) and low temperatures (-78°C in toluene or hexane).[1][75]Alpha-Deprotonation
The alpha-hydrogens adjacent to the nitrile group in compounds like acetonitrile (CH₃CN) exhibit moderate acidity, with a pKa of approximately 31 in dimethyl sulfoxide (DMSO), owing to the resonance stabilization of the conjugate carbanion by the electron-withdrawing cyano group.[76] This stabilization arises from the ability of the cyano moiety to delocalize the negative charge through overlap with its π-system, lowering the energy of the carbanion relative to the parent nitrile. The polarity of the carbon-nitrogen triple bond contributes to this electron-withdrawing effect, enhancing the acidity compared to simple alkanes (pKa ≈ 50).[77] Deprotonation of nitriles at the alpha position is typically achieved using strong, non-nucleophilic bases such as lithium diisopropylamide (LDA) or sodium hydride (NaH) to generate the corresponding alpha-lithio or sodio nitrile carbanions.[78] These carbanions, represented as R-CH⁻-CN, are highly reactive nucleophiles suitable for further synthetic elaboration. The process often employs kinetic control conditions, particularly with LDA at low temperatures (e.g., -78 °C in tetrahydrofuran), to selectively remove the less substituted alpha-proton and avoid over-deprotonation or side reactions.[79] A representative mechanism for the kinetic deprotonation of acetonitrile with LDA proceeds via rapid, irreversible abstraction of the alpha-proton, yielding the carbanion and diisopropylamine as a byproduct: This lithiated species exists in resonance with its imine tautomer but behaves primarily as a carbanion in subsequent reactions. These alpha-deprotonated nitriles find broad applications in organic synthesis, particularly for carbon-carbon bond formation through alkylation with electrophiles like alkyl halides, enabling the construction of substituted nitriles as precursors to carboxylic acids, ketones, or amines.[78] For example, sequential deprotonation and alkylation of acetonitrile can lead to mono- or dialkylated products, which are key intermediates in the synthesis of malononitrile derivatives or more complex polyfunctionalized molecules.[79]Nucleophilic Attack
Nitriles undergo nucleophilic addition reactions at the electrophilic carbon of the cyano group, driven by the polarity of the C≡N triple bond where the carbon bears a partial positive charge.[80] This reactivity enables the formation of new carbon-carbon bonds, particularly with strong nucleophiles like organometallic reagents.[81] A key example is the reaction of nitriles with Grignard reagents (RMgX) or organolithium compounds (RLi), which proceed via nucleophilic addition to yield ketones after hydrolysis.[82] The general process involves the organometallic carbon attacking the nitrile carbon, forming an imine-metal complex intermediate, represented as: \ce{R-C#N + R'-M ->{{grok:render&&&type=render_inline_citation&&&citation_id=1&&&citation_type=wikipedia}} R-C(R')=N^-M^+} Subsequent acidic hydrolysis protonates the imine and cleaves it to the corresponding ketone: \ce{R-C(R')=N^-M^+ + H3O^+ ->{{grok:render&&&type=render_inline_citation&&&citation_id=2&&&citation_type=wikipedia}} R-C(O)-R' + HM + NH4^+} where M is MgX or Li.[81] The mechanism begins with the nucleophilic organometallic carbon adding to the electrophilic nitrile carbon, displacing the triple bond electrons to form the imine anion.[80] This intermediate resists further nucleophilic attack due to the negatively charged nitrogen, ensuring selective mono-addition unlike reactions with aldehydes or ketones.[83] Hydrolysis then converts the imine to the ketone through protonation and water addition.[82] A representative example is the addition of phenylmagnesium bromide to acetonitrile: \ce{CH3-C#N + PhMgBr ->[H3O^+] CH3-C(O)-Ph} This yields acetophenone in good yield under anhydrous conditions, typically in ether solvents.[80] The scope includes aliphatic, aromatic, and heterocyclic nitriles with Grignard or organolithium reagents, providing a versatile route to unsymmetrical ketones.[81] Another manifestation of nucleophilic attack is the Thorpe reaction, a base-catalyzed self-condensation of nitriles.[84] In this process, a strong base deprotonates the alpha position of one nitrile to generate a carbanion nucleophile, which adds to the cyano carbon of a second nitrile molecule, forming a β-iminonitrile intermediate.[85] The intermolecular variant produces acyclic enaminonitriles, while the intramolecular Thorpe-Ziegler variant cyclizes di-nitriles to form 5- to 8-membered rings containing α-cyanoketone precursors after hydrolysis.[86] This reaction is particularly useful for constructing cyclic β-keto nitriles, with sodium ethoxide or alkoxides commonly employed as bases.[84]Complexation and Coordination
Nitriles serve as ligands in coordination compounds by donating the lone pair on the nitrogen atom to metal centers, forming a σ-bond. This end-on coordination mode is the most common, though side-on (η²) binding can occur in certain low-valent metal systems. The linear geometry of the C≡N group facilitates monodentate ligation, and nitriles are generally weak bases, leading to labile coordination in many complexes.[87] A representative example is the [Ag(MeCN)₄]⁺ cation, where four acetonitrile ligands surround the silver(I) ion in a tetrahedral arrangement, demonstrating the utility of simple alkyl nitriles as stabilizing ligands for soft metals. In polynuclear compounds, nitriles can adopt bridging modes, as seen in diiron complexes such as [Fe₂Cp₂(CO)₂(μ-NCCH₃)]²⁺, where the nitrile spans two metal centers via the nitrogen and carbon atoms.[87] Nitrile ligands function primarily as weak σ-donors with moderate π-acceptor capabilities, allowing back-donation from the metal d-orbitals to the low-lying π* orbital of the C≡N bond; this π-interaction contributes significantly to the bonding, often 30-50% of the total interaction energy in transition metal complexes. Upon coordination, the C≡N stretching frequency in the IR spectrum typically shifts to lower values by 20-50 cm⁻¹ in systems with substantial back-donation, such as certain tungsten(II) η²-nitrile complexes, reflecting weakening of the triple bond.[87][88] In organometallic catalysis, nitrile coordination plays a role in nickel-phosphine systems for the hydrocyanation of alkenes, where transient nitrile binding facilitates key steps like oxidative addition and reductive elimination. Acetonitrile, in particular, is a preferred solvent in coordination chemistry for synthesizing metal complexes, owing to its coordinating ability and low nucleophilicity.[45]Other Reactions
Nitriles can participate in [4+2] cycloaddition reactions analogous to the Diels-Alder reaction, where the nitrile group serves as an electron-deficient dienophile, particularly when activated by additional electron-withdrawing substituents. For instance, fumaronitrile reacts with cyclopentadiene to form the corresponding cycloadduct, demonstrating the utility of unsaturated dinitriles in thermal cycloadditions. Similarly, tetracyanoethylene undergoes efficient Diels-Alder reactions with various dienes due to its highly activated nitrile functions, yielding adducts that can be further elaborated in synthesis. These reactions are typically regioselective and proceed under mild conditions, highlighting the role of the nitrile's π-system in facilitating pericyclic processes.[89][90] The Thorpe-Ziegler reaction represents a base-catalyzed self-condensation of nitriles, extending the alpha-deprotonation reactivity to form enaminonitriles, often leading to cyclic products in the intramolecular variant. In the intermolecular Thorpe reaction, two molecules of an aliphatic nitrile condense to produce a β-enaminonitrile intermediate, which can be hydrolyzed to α,β-unsaturated ketones. The intramolecular Ziegler variant, applied to dinitriles, generates cyclic α-cyanoenamines, useful for constructing fused ring systems in natural product synthesis. The mechanism involves deprotonation at the alpha position, followed by nucleophilic addition to another nitrile and tautomerization, as supported by computational studies revising earlier proposals. This transformation is particularly effective with strong bases like sodium ethoxide or alkoxides, and the cyclic products often form five- or six-membered rings efficiently.[91][84] Photochemical reactions of nitriles under UV irradiation can generate carbon-centered radicals, enabling cascade processes where the nitrile acts as a radical acceptor. These transformations typically involve homolytic cleavage or photoinduced electron transfer, leading to addition across the C≡N bond and subsequent β-scission or cyclization. For example, alkyl nitriles participate in radical cyanoalkylation cascades, forming new C-C bonds with compatible radical precursors under visible light photoredox catalysis. Such reactions have been reviewed for their versatility in constructing complex scaffolds, with nitriles serving as stable handles for radical trapping in multi-step sequences.[92] Recent advancements post-2015 have incorporated nitriles into click chemistry variants, particularly bioorthogonal reactions for selective labeling in biological contexts. Heteroaromatic nitriles, such as 2-cyanopyridines, undergo strain-promoted cycloadditions or inverse electron-demand Diels-Alder reactions with tetrazines, offering tunable reactivity under physiological conditions. Additionally, multicomponent oxidative nitrile thiazolidination enables rapid formation of thiazolidine linkages from nitriles and amines, providing a metal-free click strategy for bioconjugation. These methods expand the toolkit for nitrile-based modular synthesis in medicinal chemistry and materials science. More recent developments as of 2025 include advances in nitrile cyclization to diverse N-heterocycles and cobalt(III)-mediated activations for drug development.[93][94][95][96]Derivatives
Organic Cyanamides
Organic cyanamides, also known as N-monosubstituted cyanamides, are organic compounds featuring a cyano group attached to an NH-R moiety, with the general structure R-\ce{NH-C#N}, where R is an organic substituent such as an alkyl or aryl group. This structure distinguishes them from simple nitriles (R-C≡N) by the presence of the nitrogen atom directly bonded to the carbon of the cyano group, resulting in a cumulative double bond system similar to the nitrile bonding in R-C≡N. The most common synthesis of organic cyanamides involves the electrophilic cyanation of primary amines using cyanogen bromide as the cyanating agent, proceeding via nucleophilic attack of the amine on the electrophilic carbon of BrCN. The reaction is typically carried out under mild conditions and can be represented by the equation:This method provides a straightforward route to N-monosubstituted cyanamides in good yields. Organic cyanamides exhibit greater basicity than simple nitriles due to the amine-like NH group, which allows for protonation or deprotonation more readily than the weakly basic nitrogen in R-C≡N. In infrared spectroscopy, they display a characteristic C≡N stretching absorption in the 2100-2200 cm⁻¹ region, slightly broader and lower in frequency compared to typical nitriles owing to the adjacent nitrogen atom. A key reaction of organic cyanamides is acid- or base-catalyzed hydrolysis, which converts them to N-monosubstituted ureas through addition of water across the cumulative bonds:
This transformation is valuable for urea synthesis. Additionally, organic cyanamides serve as crosslinkers in polymer chemistry, where their reactivity enables the formation of networked structures in materials like polyurethanes and resins. In applications, organic cyanamides act as intermediates in the synthesis of various agrochemicals and pharmaceuticals.